U.S. patent application number 10/415850 was filed with the patent office on 2004-09-09 for medicine based on anti-hyperglycaemic microcapsules with prolonged release and method for preparing same.
Invention is credited to Castan, Catherine, Meyriuex, Remi, Soula, Gerard.
Application Number | 20040175424 10/415850 |
Document ID | / |
Family ID | 8856604 |
Filed Date | 2004-09-09 |
United States Patent
Application |
20040175424 |
Kind Code |
A1 |
Castan, Catherine ; et
al. |
September 9, 2004 |
Medicine based on anti-hyperglycaemic microcapsules with prolonged
release and method for preparing same
Abstract
The invention concerns an oral galenic form for prolonged
release of anti-hyperglycaemic (metformin) active principles. Said
medicine enables to obtain an efficient therapeutic protection over
24 hours by overcoming the problems of bypass of the absorption
window and the massive localised release of active principles.
Therefor, said medicine comprises several thousand
anti-hyperglycaemic (metformin) microcapsules each consisting of a
core comprising at least an anti-hyperglycaemic agent and of a
coating film applied on the core and enabling the prolonged release
in vivo of the anti-hyperglycaemic agent. Said microcapsules have a
grain size distribution ranging between 50 and 100 microns. The
reproducibility of the transit kinetics and hence of
bioavailability are very high. There results for the patient a
lesser risk of hyperglycaemic or hypoglycaemic. The invention also
concerns the preparation of said medicine and the use of a
plurality of said microcapsules for making an anti-hyperglycaemic
medicine. The invention is applicable to the treatment of type II
diabetes.
Inventors: |
Castan, Catherine;
(Orlienas, FR) ; Meyriuex, Remi; (Lyon, FR)
; Soula, Gerard; (Meyzieu, FR) |
Correspondence
Address: |
MCCRACKEN & FRANK LLP
200 W. ADAMS STREET
SUITE 2150
CHICAGO
IL
60606
US
|
Family ID: |
8856604 |
Appl. No.: |
10/415850 |
Filed: |
June 6, 2003 |
PCT Filed: |
November 17, 2001 |
PCT NO: |
PCT/FR01/03625 |
Current U.S.
Class: |
424/470 ;
424/490 |
Current CPC
Class: |
A61K 31/00 20130101;
A61K 31/155 20130101; A61P 3/10 20180101; A61P 9/12 20180101; A61K
9/5015 20130101; A61K 9/5047 20130101 |
Class at
Publication: |
424/470 ;
424/490 |
International
Class: |
A61K 009/26; A61K
009/16; A61K 009/50 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 17, 2000 |
FR |
00/14876 |
Claims
1. A medicament based on at least one anti-hyperglycemic which can
be administered by the oral route, characterized: in that it
comprises a plurality of micro-capsules each composed of a core
comprising at least one antihyperglycemic and of a coating film
applied to the core and which makes possible the prolonged release
in vivo of the antihyperglycemic(s), with the exclusion of the
coating films composed of enteric compositions and of the coating
films with the following composition: 1--at least one film-forming
polymer (P1) which is insoluble in the liquids of the tract,
present in a proportion of 50 to 90%, preferably 50 to 80%, by
weight on a dry basis with respect to the total mass of the coating
composition and composed of at least one water-insoluble derivative
of cellulose, namely ethylcellulose and/or cellulose acetate; 2--at
least one nitrogenous polymer (P2), present in a proportion of 2 to
25%, preferably 5 to 15%, by weight on a dry basis with respect to
the total mass of the coating composition and composed of at least
one polyacrylamide and/or one poly-N-vinylamide and/or one
poly-N-vinyllactam, namely polyacrylamide and/or
polyvinylpyrrolidone; 3--at least one plasticizer, present in a
proportion of 2 to 20%, preferably of 4 to 15%, by weight on a dry
basis with respect to the total mass of the coating composition and
composed of at least one of the following compounds: glycerol
esters, phthalates, citrates, sebacates, esters of cetyl alcohol,
castor oil, salicylic acid and cutin; 4--and optionally at least
one surface-active and/or lubricating agent, present in a
proportion of 2 to 20%, preferably of 4 to 15%, by weight on a dry
basis with respect to the total mass of the coating composition and
chosen from anionic surfactants, namely alkali metal or alkaline
earth metal salts of fatty acids, stearic acid and/or oleic acid
being preferred, and/or from nonionic surfactants, namely
polyoxyethylenated sorbitan esters and/or polyoxyethylenated castor
oil derivatives, and/or from lubricating agents, such as calcium
stearate, magnesium stearate, aluminum stearate or zinc stearate,
or such as sodium stearylfumarate and/or glycerol behenate; it
being possible for said agent to comprise just one or a mixture of
abovesaid products; in that these microcapsules have a particle
size of between 50 and 1000 microns, preferably between 100 and 750
microns and more preferably still between 200 and 500 microns.
2. The medicament as claimed in claim 1, characterized in that the
size and the coating of the microcapsules are chosen so that,
everything else otherwise being equal, its bioavailability during
oral administration on a full stomach is at least equal to its
bioavailability during oral administration on an empty stomach.
3. The medicament as claimed in claim 1 or 2, characterized in that
the mean fraction by mass of antihyperglycemic in the microcapsules
is greater than 50%, preferably greater than or equal to 60%.
4. The medicament any one of claims 1 to 3, characterized in that
the antihyperglycemic is chosen from biguanides, preferably from
the group of biguanides comprising metformin and buformin and their
salts, metformin and its salts being particularly preferred.
5. The medicament as claimed in any one of claims 1 to 4,
characterized in that, in an in vitro dissolution test known as the
type II dissolutest in accordance with the Pharmacopoeia, the
dissolution of the antihyperglycemic(s) extends over at least 8
hours, preferably at least 20 hours.
6. The medicament as claimed in any one of claims 1 to 5,
characterized in that it exists in the form of a tablet which can
disintegrate in the mouth or, by effervescence or not by
effervescence, in a liquid, of a powder, of a suspension or of a
gelatin capsule.
7. The medicament as claimed in any one of claims 1 to 6,
characterized in that it is composed of a pharmaceutical dosage
form, the dose of antihyperglycemic(s) of which is between 800 and
1200 mg, preferably between 900 and 1100 mg and more preferably
still of the order of 1000 mg.
8. The medicament as claimed in any one of claims 1 to 7,
characterized in that this multimicrocapsule medicament is composed
of several thousand microcapsules as defined in the preceding
claims, this multiplicity providing good reproducibility of the
gastrointestinal transit of the anti-hyperglycemic, thus reducing
the risk to the patient of hypo- or hyperglycemia.
9. The medicament as claimed in any one of claims 1 to 8,
characterized in that the core of the micro-capsules is a granule
comprising antihyperglycemic(s) and granulation excipients and/or a
particle of substantially pure antihyperglycemic(s), preferably a
monocrystal of antihyperglycemic(s).
10. The medicament as claimed in any one of claims 1 to 9,
characterized in that the coating film comprises one or more
products selected from the group consisting of: film-forming
macromolecules, preferably chosen from the group consisting of:
cellulose ethers, cellulose ethers/esters, cellulose esters,
cellulose diesters, cellulose triesters, cellulose acylate,
cellulose diacylate, cellulose triacylate, cellulose diacetate and
triacetate, cellulose acetate/propionate, cellulose
acetate/butyrate, polymethacrylates, waxes and vinyl acetate
copolymers; ethylcellulose, Eudragit.RTM. RS, Eudragit.RTM. RL and
cellulose acetate being particularly preferred; plasticizers,
preferably chosen from the following nonexhaustive list: tributyl
acetylcitrate, triethyl acetylcitrate, acetylated glycerides,
castor oil, dibutyl phthalate, diethyl phthalate, diethyl sebacate,
dibutyl sebacate, dimethyl phthalate, glycerol, glycerol
monostearate, glyceryl triacetate, polyethylene glycol,
polyoxyethylene/polyoxypropylene copolymers, propylene glycol,
tributyl citrate, triethyl citrate, adipate, azelate, enzoate,
citrate, citric acid esters, triacetin, vegetable oils, glycerin
sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate,
dibutyl succinate, diethyl malonate, dioctyl phthalate or glycerol
tributyrate; and optionally other excipients selected from soluble
or insoluble fillers (talc, inorganic salts, sugars,
polyvinylpyrrolidone, polyethylene glycol, and the like),
lubricants, dyes or pigments.
11. The medicament as claimed in claim 10, characterized in that
the film-forming macromolecules constituting the film coating are
combinations of cellulose derivatives and of at least one
pharmaceutically acceptable hydrophilic polymer, the fraction by
mass of cellulose derivatives preferably being between 30 and 90%
and more preferably still between 50 and 80%.
12. A process for the preparation of the medicament as claimed in
any one of claims 1 to 9, characterized in that it consists: in
employing granules comprising antihyperglycemic(s) and granulation
excipients or alternatively particles of substantially pure
antihyperglycemic(s), preferably monocrystals of
antihyperglycemic(s); and in then spraying, over these granules
and/or these particles, a coating solution comprising one or more
products selected from the group consisting of: film-forming
macromolecules, preferably chosen from the group consisting of:
cellulose ethers, cellulose ethers/esters, cellulose esters,
cellulose diesters, cellulose triesters, cellulose acylate,
cellulose diacylate, cellulose triacylate, cellulose diacetate and
triacetate, cellulose acetate/propionate, cellulose
acetate/butyrate, polymethacrylates, waxes and vinyl acetate
copolymers; ethylcellulose, Eudragit.RTM. RS, Eudragit.RTM. RL and
cellulose acetate being particularly preferred; plasticizers,
preferably chosen from the following nonexhaustive list: tributyl
acetylcitrate, triethyl acetylcitrate, acetylated glycerides,
castor oil, dibutyl phthalate, diethyl phthalate, diethyl sebacate,
dibutyl sebacate, dimethyl phthalate, glycerol, glycerol
monostearate, glyceryl triacetate, polyethylene glycol,
polyoxyethylene/polyoxypropylen- e copolymers, propylene glycol,
tributyl citrate, triethyl citrate, adipate, azelate, enzoate,
citrate, citric acid esters, triacetin, vegetable oils, glycerin
sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate,
dibutyl succinate, diethyl malonate, dioctyl phthalate or glycerol
tributyrate; and optionally other excipients selected from soluble
or insoluble fillers (talc, inorganic salts, sugars,
polyvinylpyrrolidone, polyethylene glycol, and the like),
lubricants, dyes or pigments.
13. Use of a plurality of microcapsules: each composed of a core
comprising at least one antihyperglycemic and of a coating film
applied to the core and which makes possible the prolonged release
in vivo of the antihyperglycemic(s), and having a particle size of
between 50 and 1000 microns, preferably between 100 and 750 microns
and more preferably still between 200 and 500 microns; for
manufacturing a medicament based on at least one antihyperglycemic
which can be administered by the oral route, which can be easily
swallowed and which contributes to the control of glycemia over at
least 12 h in a reliable manner and while limiting problems of
bypass, of accumulation and of localized and massive release of
antihyperglycemic.
Description
[0001] The field of the present invention is that of oral
pharmaceutical dosage forms which make possible the prolonged
release of antihyperglycemic active principles. More specifically,
the present invention relates to a novel medicament which can be
administered by the oral route and which makes possible the
prolonged release in vivo of a biguanide, such as metformin or
buformin, or any pharmaceutically acceptable salt of these
compounds, such as, for example, metformin hydrochloride.
[0002] The term "prolonged-release oral pharmaceutical dosage
forms" is understood to mean the oral pharmaceutical dosage forms
which make possible a slowed release of active principles in
comparison with the conventional pharmaceutical dosage forms
administered according to the same route. This definition is that
given by the European Agency for the Evaluation of Medicinal
Products in its Note on the Quality of Modified Release Products of
29 Jul. 1999.
[0003] This definition excludes delayed-release oral pharmaceutical
dosage forms, which consist of pharmaceutical dosage forms which
make it possible to delay the release of the active principles for
a predetermined period of time after administration, this release,
equivalent to that of the conventional pharmaceutical dosage forms,
then resulting from a time lag without modification of the other
pharmacokinetic parameters (Note on the Quality of Modified Release
Products of 29 Jul. 1999, European Agency for the Evaluation of
Medicinal Products).
[0004] The prior art comprises numerous technical proposals for
producing prolonged-release forms of pharmaceutical products with
the aim of extending the duration of the therapeutic coverage and
of improving the comfort of the patients and the probability of
them observing the dosage. However, very few studies have been
devoted to developing controlled-release antihyperglycemic
forms.
[0005] These antihyperglycemics, and in particular metformin
hydrochloride, exhibits a low intrinsic permeability in the distal
parts of the gastrointestinal tract. Its absorption therefore takes
place essentially in the upper part of the gastrointestinal tract.
Its oral bioavailability is of the order of 40 to 60%. It decreases
when the dose increases, which suggests a saturable absorption or
an absorption limited by the permeability and the transit time.
Products exhibiting an absorption limited to the upper part of the
gastrointestinal tract, which are said to "have an absorption
window", are regarded as poor candidates for prolonged-release oral
forms. The administration of these products by a conventional
prolonged-release system can actually be reflected by plasma
concentrations below the therapeutic threshold and thus with an
ineffective treatment.
[0006] Another characteristic of these antihyperglycemics, such as
metformin hydrochloride, is their very high solubility in water:
more than 300 g/l at 25.degree. C. This presents problems when it
is a question of obtaining a formulation exhibiting a low and fully
controlled rate of release, without sudden discharge (burst
effect). To overcome this, it is generally necessary to use large
amounts of polymers to form a matrix or a barrier capable of
sufficiently slowing down the release of the metformin to produce
the desired plasma concentration profile and, in this case, the
formulator has every interest in favoring the monolithic forms,
which offer less surface area to the diffusion of the active
principle.
[0007] Furthermore, the daily dose of active principle can be of
the order of one gram. This is the case in particular for
metformin. The result of this is that the prolonged-release forms
of metformin, inter alia, can be of large size. Such a large
monolithic unit form can undergo random gastric emptying and can
therefore remain for a poorly controlled time upstream of its
absorption window. This results in a random and poorly controlled,
in amount and duration, absorption of the active principle.
Frequent disappointments (bypass) of this type have the
consequence, in the case of antihyperglycemics, that glycemia may
not be correctly controlled, which can have extremely harmful
consequences for the diabetic patient.
[0008] The large monolithic pharmaceutical dosage form may also be
found blocked in the twists and turns of the gastrointestinal
tract. A massive and highly localized release of the active
principle then occurs (dose dumping), which active principle not
only will not be absorbed according to the desired profile but,
moreover, is capable of causing local injuries to the tissues at
the spot of the massive release.
[0009] Thus, the prior art only discloses monolithic forms capable
of remaining for a certain time in the stomach (gastroretention),
so as to release the metformin upstream of its absorption
window.
[0010] Patent application WO 98/55107 discloses tablets comprising
a matrix formed of hydrophilic polymer of high molecular weight
(polyoxyethylene) comprising metformin. Once ingested, this matrix
swells to large dimensions (e.g. 7.2 mm in diameter.times.8.8 mm in
length), promoting its retention by the stomach, while limiting the
rate of dissolution of the metformin.
[0011] Patent WO 99/47125 discloses a controlled-release monolithic
tablet formed:
[0012] of a core comprising:
[0013] the antihyperglycemic active principle (metformin),
[0014] a water-insoluble binding agent (polyvinylpyrrolidone),
[0015] an absorption promoter (bile salt),
[0016] and of a semipermeable membrane (insoluble cellulose
derivative) coating the core and pierced by at least one hole.
[0017] Conventionally, in techniques for the manufacture of
tablets, the tablets according to WO 99/47125 are obtained from
uncoated granules, prepared by wet granulation, that is to say
agglomeration of metformin particles using the abovementioned
binding agent. The granules have a size significantly greater than
that of the starting metformin particles.
[0018] This pharmaceutical dosage form is supposed to have a
therapeutic coverage over 24 hours after oral administration on a
full stomach.
[0019] One of the disadvantages of this pharmaceutical dosage form
is the presence of this absorption promoter, which can weaken the
intestinal wall and can, over prolonged administration, have
undesirable side effects.
[0020] Another disadvantage is that this "tablet" form has a
variable gastric residence time, unlike a microparticle
pharmaceutical dosage form, the residence time of which is kept in
balance by the large number of particles.
[0021] Patent WO 99/47128 discloses a prolonged-release oral
pharmaceutical dosage form which makes possible prolonged residence
in the stomach.
[0022] It is a form suitable for active principles possessing high
solubility in water and exhibiting an absorption window limited to
the top part of the gastrointestinal tract (metformin). This is a
two-phase system and comprises:
[0023] a particulate internal phase formed of individual granules
charged with AP. The distinctive feature of these granules is that
they are uncoated and comprise one or more excipients which can
be:
[0024] a hydrophobic polymer: copolymer of (meth)acrylic acid
(Eudragit.RTM.), ethylcellulose,
[0025] and/or a hydrophilic polymer: sodium carboxymethylcellulose
or sodium alginate,
[0026] and/or other hydrophobic compounds: waxes, fatty alcohols,
fatty acid esters, and an external solid continuous phase in which
the particles of the internal phase are embedded, this external
continuous solid phase comprising:
[0027] one or more hydrophilic polymers:
[hydroxypropylmethylcellulose --HPMC--(with a viscosity of 5 cPs
and 1.times.10.sup.5 cPs), microcrystalline cellulose],
[0028] and/or one or more hydrophobic polymers,
[0029] and/or one or more other hydrophobic compounds (waxes, fatty
alcohols, fatty acid esters).
[0030] This pharmaceutical dosage system is preferably in the form
of oblong tablets. It is presented as having an increased residence
time in the top part of the gastrointestinal tract (stomach/small
intestine) by an effect of increase in size, without, however,
achieving an upper limit resulting in blockage.
[0031] One disadvantage of this pharmaceutical dosage form is that
it exhibits a variable gastric residence time, unlike a
microparticle pharmaceutical dosage form, the residence time of
which is kept in balance by the large number of particles.
[0032] Furthermore, it is probable that this pharmaceutical dosage
system according to WO 99/47128 (preferably a tablet) has a low
mechanical strength in a gastric environment. In such an event, the
release of the AP would no longer be controlled.
[0033] These three inventions refer to large monolithic forms which
have to be ingested as such. Thus:
[0034] for a dose of 1 g of metformin: patent WO 98/55107 provides
8 tablets 10.4.times.6.6 mm present in 4 gelatin capsules;
[0035] for a dose of 1 g of metformin: patent WO 99/47128 provides
2 large oblong tablets;
[0036] for a dose of 850 mg of metformin: patent WO 99/47125
provides a tablet with a diameter of 12 mm.
[0037] Problems of observance may be encountered with these forms
for patients having difficulties in swallowing.
[0038] Furthermore, the plasma concentration profile obtained from
these systems is highly conditioned by the residence time in the
stomach, which can be the subject of large interindividual
variations. The monolithic systems are subject to and sometimes
accentuate the effect of these interindividual variations, which
can result in the treatment being ineffective in a not
insignificant portion of the population treated.
[0039] Finally, these pharmaceutical dosage systems are capable of
resulting either in problems of bypass of the absorption window or
in problems of localized accumulation of the active principle, and
of subsequent injuries.
[0040] PCT Application WO 96/11675 discloses medicinal and/or
nutritional microcapsules for the administration per os of active
principle, with the exception of aspirin and without any details of
a specific class of active principles, namely antihyperglycemics
and in particular metformin. These medicinal microcapsules are
composed of particles of active principle (without
antihyperglycemics being specified), each covered with a coating
film comprising at least one film-forming polymer P1, at least one
nitrogenous polymer P2, at least one plasticizer and at least one
surfactant and/or lubricant. The medicinal microcapsules according
to WO 96/11675 do not solve the specific problem of the therapeutic
coverage over 24 hours of antihyperglycemics and with an absorption
window in the top parts of the gastrointestinal tract, which are
very soluble in water and which have to be ingested at high doses
each time they are taken (1 g per day).
[0041] The document WO 00/28989 discloses delayed-release
compositions which are provided in the form of gelatin capsules
comprising multiple cores of granules comprising an insulin
sensitization agent and another antidiabetic agent, which can be a
biguanide, such as metformin. The cores of granules can be coated
with an enteric composition and in particular a composition
composed of a film-forming polymer, such as Eudragit L100-55.
However, this document does not disclose an antihyperglycemic
medicament which can be administered per os, which is provided in
the form of microparticles which make possible the prolonged
release of the antihyperglycemic active principle or
principles.
[0042] In such a state of the art, one of the essential objectives
of the present invention is to provide a novel pharmaceutical
dosage system for the oral administration of antihyperglycemic
active principles, this system having to make it possible to obtain
an effective therapeutic coverage over 24 hours while overcoming
the problems of bypass of the absorption window and of massive
localized release of active principle.
[0043] One objective of the present invention is to provide a
pharmaceutical form composed of a large number, of the order of
several thousand, of antihyperglycemic microcapsules and in
particular metformin microcapsules, this multiplicity of
microcapsules statistically providing good reproducibility of the
kinetics of transit of the antihyperglycemic (metformin) throughout
the gastrointestinal tract. This results in better control of the
bioavailability and thus, for the patient, in a reduced risk of
hyperglycemia or of hypoglycemia.
[0044] One objective of the present invention is to provide a
prolonged-release antihyperglycemic, and in particular metformin,
multimicrocapsule pharmaceutical dosage form, this pharmaceutical
dosage form being composed of a tablet which is dispersible in a
liquid or in the mouth, of an effervescent tablet or of powder in
sachets.
[0045] Another objective of the present invention is to provide a
prolonged-release antihyperglycemic, and in particular metformin,
multimicrocapsule form which results, after oral administration, in
a plasma peak after more than 6 hours approximately.
[0046] Another objective of the present invention is to provide a
prolonged-release antihyperglycemic, and in particular metformin,
multimicrocapsule form, the bioavailability of this not being
reduced by administration on a full stomach.
[0047] Another objective of the present invention is to provide a
prolonged-release antihyperglycemic, and in particular metformin,
multimicrocapsule form which provides sufficient therapeutic
coverage for administration of the active principle once or twice
daily.
[0048] Another object of the present invention is to obtain a
multimicrocapsule system which provides for the in vitro release of
the antihyperglycemic products over more than 8 hours while
avoiding the use of large amounts of polymers, the active principle
content remaining comparable to, indeed even greater than, that of
monolithic forms.
[0049] Another object of the present invention is to provide a
simple and economic process for the preparation of the
abovementioned multimicrocapsule pharmaceutical dosage form.
[0050] The objectives stated above, among others, are obtained by
the invention, which provides, first, a medicament based on at
least one antihyperglycemic which can be administered by the oral
route, characterized:
[0051] in that it comprises a plurality of microcapsules each
composed of a core comprising at least one antihyperglycemic and of
a coating film applied to the core and which makes possible the
prolonged release in vivo of the antihyperglycemic(s),
[0052] with the exclusion of the coating films composed of enteric
compositions and of the coating films with the composition
following:
[0053] 1--at least one film-forming polymer (P1) which is insoluble
in the fluids of the tract, present in a proportion of 50 to 90%,
preferably 50 to 80%, by weight on a dry basis with respect to the
total mass of the coating composition and composed of at least one
water-insoluble cellulose derivative of cellulose, namely
ethylcellulose and/or cellulose acetate;
[0054] 2--at least one nitrogenous polymer (P2), present in a
proportion of 2 to 25%, preferably 5 to 15%, by weight on a dry
basis with respect to the total mass of the coating composition and
composed of at least one polyacrylamide and/or one
poly-N-vinylamide and/or one poly-N-vinyllactam, namely
polyacrylamide and/or polyvinylpyrrolidone;
[0055] 3--at least one plasticizer, present in a proportion of 2 to
20%, preferably of 4 to 15%, by weight on a dry basis with respect
to the total mass of the coating composition and composed of at
least one of the following compounds: glycerol esters, phthalates,
citrates, sebacates, esters of cetyl alcohol, castor oil, salicylic
acid and cutin;
[0056] 4--and optionally at least one surface-active and/or
lubricating agent, present in a proportion of 2 to 20%, preferably
of 4 to 15%, by weight on a dry basis with respect to the total
mass of the coating composition and chosen from anionic
surfactants, namely alkali metal or alkaline earth metal salts of
fatty acids, stearic acid and/or oleic acid being preferred, and/or
from nonionic surfactants, namely polyoxyethylenated sorbitan
esters and/or polyoxyethylenated castor oil derivatives, and/or
from lubricating agents, such as calcium stearate, magnesium
stearate, aluminum stearate or zinc stearate, or such as sodium
stearylfumarate and/or glycerol behenate; it being possible for
said agent to comprise just one or a mixture of abovesaid
products;
[0057] in that these microcapsules have a particle size of between
50 and 1000 microns, preferably between 100 and 750 microns and
more preferably still between 200 and 500 microns.
[0058] The term "enteric compositions" is understood to mean the
compositions which confer on the coating a resistance to acidic pH
(gastric pH) and which make possible release of the active
principle or principles when the pH is raised.
[0059] Thus, the medicament according to the invention is
particularly suitable for antihyperglycemic active principles which
have the characteristic of having an absorption window situated in
the top parts of the gastrointestinal tract (stomach and start of
the small intestine), which are very soluble in water and for which
the dosage is of the order of 1 g per day, which requires the
ingestion of a large amount of product each time it is taken.
[0060] This medicament, in a "multimicrocapsule" pharmaceutical
dosage form composed of a plurality of microcapsules, necessarily
restricts, for statistical reasons, the risk of bypass of the
absorption window and eliminates the risk of localized accumulation
of active principle. This results in an optimum absorption of
antihyperglycemics in the absorption window, in an amount such that
and over a time such that the therapeutic coverage can be
guaranteed over at least 12 h with all the therapeutic safety
desirable (control of glycemia). This is because the large number
of particles (e.g. of the order of 10 000) makes possible a
reproducible distribution, thus reducing the risks of hyper- and
hypoglycemia.
[0061] The antihyperglycemics more particularly affected by the
invention are those chosen within the group consisting of metformin
and its salts, such as metformin hydrochloride.
[0062] The appended FIGS. 1 and 2 are photographs (respectively
before and after a dissolution test, cf. examples below) on several
constituent microcapsules of the medicament according to the
invention. These photos clearly show that each individual
microcapsule comprises a core wrapped in a coating film which
controls the prolonged release of the antihyperglycemic active
principle or principles.
[0063] The size of each microcapsule is less than 1 mm and in
practice between 200 and 500 .mu.m, as is apparent in the photo of
FIG. 1. It should be emphasized that this is not a matter of an
agglomerate of particles of antihyperglycemics in granules with a
size of greater than 1 mm and for which the matrix is formed by a
polymer binder.
[0064] The medicament according to the invention relates to dry
pulverulent forms or forms in suspension in a liquid or
alternatively forms disintegrated in the mouth or in a liquid.
[0065] In fact, the medicament according to the invention can be
categorized as a novel "multimicrocapsule" pharmaceutical dosage
system intended to be easy to administer per os and which makes
possible prolonged release in vivo, guaranteeing therapeutic
coverage of at least 12 hours and, preferably, over at least 24
hours.
[0066] The size and the coating of the microcapsules are preferably
chosen so that, everything else otherwise being equal, its
bioavailability during oral administration on a full stomach is at
least equal to its bioavailability during oral administration on an
empty stomach.
[0067] According to a preferred characteristic of the invention,
the coating film for the microcapsules is designed so that, after
ingestion of a given dose of antihyperglycemic, the time (Tmax)
corresponding to the maximum plasma concentration in the curve of
the plasma concentration as a function of time is greater than or
equal to 6 hours, and the bioavailability, given by the area under
the curve (AUC), is greater than or equal to 60%, preferably 80%,
with respect to that obtained with the same dose of
immediate-release antihyperglycemic.
[0068] Curves of this type, which give the plasma concentration as
a function of time elapsed after ingestion, describe the
therapeutic coverage and the therapeutic effectiveness of the
medicament. There are grounds for recording that they are entirely
satisfactory for the multimicrocapsule and antihyperglycemic
medicament according to the invention.
[0069] Thus, the medicament according to the invention offers
entirely advantageous prospects in the treatment of type II
diabetes, alone or in combination with other antidiabetic
medicaments, such as insulin.
[0070] In an entirely surprising and unexpected way, the oral
multimicrocapsule pharmaceutical dosage system according to the
invention does not require the use of large amounts of excipient
polymers in relation to the mass of antihyperglycemics. Contrary to
the situation for known pharmaceutical dosage systems of monolithic
type with large dimensions.
[0071] Thus, according to an advantageous provision of the
invention, the mean fraction by mass of antihyperglycemic in the
microcapsules is greater than 50%, preferably greater than or equal
to 60%.
[0072] The technical problems solved by the invention are more
specifically those encountered for antihyperglycemics and in
particular those chosen from biguanides, preferably from the group
of biguanides comprising metformin and buformin and their salts,
metformin and its salts being particularly preferred.
[0073] The medicament according to the invention can also be
defined by characteristics of in vitro release of the
antihyperglycemic(s), by dissolution in an aqueous medium of the
coating film. From which it results that, in an in vitro
dissolution test known as the type II dissolutest in accordance
with the Pharmacopoeia, the dissolution of the antihyperglycemic
extends over at least 8 hours, preferably at least 20 hours.
[0074] The multimicrocapsule medicament according to the invention
can exist in various pharmaceutical dosage forms, including in
particular:
[0075] tablets which can disintegrate in the mouth,
[0076] tablets which can disintegrate by effervescence in a liquid
(water),
[0077] tablets which can disintegrate in a liquid (water),
[0078] powders of given doses packaged in sachets,
[0079] suspensions of microcapsules in a liquid (water),
[0080] gelatin capsules comprising a powder formed of
microcapsules.
[0081] According to a specific but nonlimiting embodiment of the
invention, the multimicrocapsule medicament is composed of a
pharmaceutical dosage form, the dose of antihyperglycemic of which
is between 800 and 1200 mg, preferably between 900 and 1100 mg and
more preferably still of the order of 1000 mg.
[0082] Such a dose is particularly suitable for the treatment of
type II diabetes, according to an effective dosage which makes it
possible to contribute to maintaining glycemia at acceptable levels
24 hours after the medicament has been taken.
[0083] This multimicrocapsule medicament, the antihyperglycemic
dose of which is between 800 and 1200 mg, preferably between 900
and 1100 mg and more preferably still of the order of 1000 mg, is
advantageously composed of several thousand microcapsules as
defined above, this multiplicity providing good reproducibility of
the gastrointestinal transit of the antihyperglycemic, thus
reducing the risk to the patient of hypo- or hyperglycemia.
[0084] To give a few details of the structure of the microcapsules,
it is specified that the core of said microcapsules can be, for
example, a granule comprising antihyperglycemic and granulation
excipients and/or a particle of antihyperglycemic, preferably a
monocrystal.
[0085] In the core of the microcapsules, the antihyperglycemic can
be used in combination with one or more excipients. This is in
particular the case when the core is composed of a granule. The
excipients then employed are those which are conventional in
granulation.
[0086] In practice, the film coating deposit on each granule can be
composed of one or more film-forming macromolecules well known to a
person skilled in the art for preparing prolonged-release forms.
For example, and without the list being exhaustive, it can be
chosen from the following families: cellulose ethers, cellulose
ethers/esters, cellulose esters, cellulose diesters, cellulose
triesters, cellulose acylate, cellulose diacylate, cellulose
triacylate, cellulose diacetate and triacetate, cellulose
acetate/propionate, cellulose acetate/butyrate, polymethacrylates,
waxes and vinyl acetate copolymers.
[0087] Preferably, the film-forming macromolecule is
ethylcellulose, Eudragit.RTM. RS, Eudragit.RTM. RL or cellulose
acetate.
[0088] More preferably still, use will be made of the combinations
of cellulose derivatives and of at least one pharmaceutically
acceptable hydrophilic polymer.
[0089] The fraction by mass of cellulose derivatives is
advantageously between 30 and 90% and more advantageously still
between 50 and 80%.
[0090] The film coating can also comprise the excipients commonly
used as plasticizers. They can be chosen from the following
nonexhaustive list: tributyl acetylcitrate, triethyl acetylcitrate,
acetylated glycerides, castor oil, dibutyl phthalate, diethyl
phthalate, diethyl sebacate, dibutyl sebacate, dimethyl phthalate,
glycerol, glycerol monostearate, glyceryl triacetate, polyethylene
glycol, polyoxyethylene/polyoxypropylen- e copolymers, propylene
glycol, tributyl citrate, triethyl citrate, adipate, azelate,
enzoate, citrate, citric acid esters, triacetin, vegetable oils,
glycerin sorbitol, diethyl oxalate, diethyl malate, diethyl
fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate or
glycerol tributyrate.
[0091] Other commonly used excipients can be introduced into the
coating, such as soluble or insoluble fillers (talc, inorganic
salts, sugars, polyvinylpyrrolidone, polyethylene glycol, and the
like), lubricants, dyes or pigments.
[0092] According to another of its aspects, the invention is
targeted at the process for the preparation of the medicament as
defined above.
[0093] This process consists:
[0094] in employing granules comprising antihyperglycemic(s) and
granulation excipients or alternatively particles of substantially
pure antihyperglycemic(s), preferably monocrystals of
antihyperglycemic(s);
[0095] and in then spraying, over these granules and/or these
particles, a coating solution comprising one or more products
selected from the group consisting of:
[0096] film-forming macromolecules, preferably chosen from the
group consisting of:
[0097] cellulose ethers, cellulose ethers/esters, cellulose esters,
cellulose diesters, cellulose triesters, cellulose acylate,
cellulose diacylate, cellulose triacylate, cellulose diacetate and
triacetate, cellulose acetate/propionate, cellulose
acetate/butyrate, polymethacrylates, waxes and vinyl acetate
copolymers;
[0098] ethylcellulose, Eudragit.RTM. RS, Eudragit.RTM. RL and
cellulose acetate being particularly preferred;
[0099] plasticizers, preferably chosen from the following
nonexhaustive list: tributyl acetylcitrate, triethyl acetylcitrate,
acetylated glycerides, castor oil, dibutyl phthalate, diethyl
phthalate, diethyl sebacate, dibutyl sebacate, dimethyl phthalate,
glycerol, glycerol monostearate, glyceryl triacetate, polyethylene
glycol, polyoxyethylene/polyoxypropylene copolymers, propylene
glycol, tributyl citrate, triethyl citrate, adipate, azelate,
enzoate, citrate, citric acid esters, triacetin, vegetable oils,
glycerin sorbitol, diethyl oxalate, diethyl malate, diethyl
fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate or
glycerol tributyrate;
[0100] and optionally other excipients selected from soluble or
insoluble fillers (talc, inorganic salts, sugars,
polyvinylpyrrolidone, polyethylene glycol, and the like),
lubricants, dyes or pigments;
[0101] using a technology provided for this purpose and known to a
person skilled in the art, such as that involving a Wurster.RTM.
system from Glatt or a Precisiocoater.RTM. system from
Aeromatic.
[0102] As already indicated above, the granules capable of forming
the core of the microcapsules are obtained by conventional
granulation techniques.
[0103] The granulation excipients employed are well known to a
person skilled in the art and are in particular those exemplified
above.
[0104] The innovative characteristics of the process result from
the materials employed and from the combination of the carefully
selected physical parameters.
[0105] In accordance with the invention, provision is also made, as
solution to the problems mentioned at the beginning of the present
account, namely: bypass of the absorption window, massive and
localized release of the antihyperglycemic, pharmaceutical dosage
form which can be easily swallowed, everything from the viewpoint
of effective and certain therapeutic coverage for at least 12 h
(control of glycemia), to use a plurality of microcapsules:
[0106] each composed of a core comprising at least one
antihyperglycemic and of a coating film applied to the core and
which makes possible the prolonged release in vivo of the
antihyperglycemic(s),
[0107] and having a particle size of between 50 and 1000 microns,
preferably between 100 and 750 microns and more preferably still
between 200 and 500 microns;
[0108] for manufacturing a medicament based on at least one
antihyperglycemic which can be administered by the oral route,
which can be easily swallowed and which contributes to the control
of glycemia (reduction in the risk of hypo- or hyperglycemia) over
at least 12 h in a reliable manner, while limiting problems of
bypass, of accumulation and of localized and massive release of
antihyperglycemic.
[0109] According to yet another of its subject matters, the present
invention relates to a method for the treatment of type II
diabetes, in which recourse is had to a medicament as defined above
as product per se or as product obtained by the process described
above.
[0110] The examples which follow will make possible a better
understanding of the invention and an apprehension of all these
advantages and all its alternative embodiments.
EXAMPLES
DESCRIPTION OF THE FIGURES
[0111] FIGS. 1 and 2 are photographs of microcapsules respectively
before and after the dissolutest dissolution test employed and
defined in the examples.
[0112] FIG. 3 is a curve giving the percentage of dissolution
(dissolutest) as a function of time of metformin microcapsules
according to example 1.
[0113] FIG. 4 is a curve giving the percentage of dissolution
(dissolutest) as a function of time of metformin microcapsules
according to example 2.
EXAMPLE 1
[0114] 159.5 g of stearic acid and 159.5 g of ethylcellulose are
dissolved in 2870 g of isopropanol maintained at 50.degree. C. This
solution is sprayed over 700 g of metformin.HCl crystals with a
mean diameter of between 100 and 200 .mu.m charged to a Glatt GPCG1
spray coater. The film-coating conditions are: product temperature:
38-42.degree. C., rate of spraying: 10 g/min, atomization pressure:
2 bar.
[0115] The microcapsules obtained were tested in a type II
dissolutest in accordance with the Pharmacopoeia in a
KH.sub.2PO.sub.4/NaOH buffer medium at pH 6.8, maintained at
37.degree. C. and stirred at 10 revolutions/min.
[0116] It turns out that the microcapsules were not modified
externally by the dissolution test. This proves that they indeed
comprise a coating through which the metformin diffused during the
dissolution test and which was not affected by the dissolution.
[0117] The dissolution profile obtained is as follows:
1 TABLE 1 Time Metformin dissolved (hour) (%) 2 14.7 4 34.4 8 69.4
12 87.5 16 94.3 20 97.1
[0118] The dissolution profile of the product prepared in this
example is represented in FIG. 3.
EXAMPLE 2
[0119] 51.13 g of ethylcellulose and 5.73 g of castor oil are
dissolved in a mixture of 393 g of acetone and 262 g of
isopropanol. This solution is sprayed over 200 g of metformin.HCl
crystals with a mean diameter of between 200 and 500 .mu.m charged
to a Niro CC1 spray coater. The film-coating conditions are:
product temperature: 38-42.degree. C., rate of spraying: 4 g/min,
atomization pressure: 1 bar.
[0120] The microcapsules obtained were tested in a type II
dissolutest in accordance with the Pharmacopoeia in a
KH.sub.2PO.sub.4/NaOH buffer medium at pH 6.8, maintained at
37.degree. C. and stirred at 10 revolutions/min.
[0121] The dissolution profile obtained is as follows:
2 TABLE 2 Time Metformin dissolved (hour) (%) 2 29.4 4 56.0 8 85.2
12 93.6 16 96.9 20 98.7
[0122] The dissolution profile of the product prepared in this
example is represented in FIG. 4.
EXAMPLE 3
[0123] Two gelatin capsules with a size of 00, each comprising 500
mg of coated metformin in the microcapsules described in example 2,
or else 4 Glucophage tablets, each comprising 250 mg of metformin,
are administered to 12 healthy subjects after eating with 250
ml.
[0124] Blood samples are taken at 0, 0.5, 1, 2, 3, 4, 5, 6, 8, 10,
12, 16, 20, 24 and 36 hours after administration in order to
analyze the metformin concentration.
[0125] The mean plasma concentration profile demonstrates an
increase in the time corresponding to the plasma concentration
maximum, this being achieved without a very significant decrease in
the bioavailability evaluated by the area under the plasma
concentration profile between the points and 36 hours.
[0126] The main pharmacokinetic parameters are listed in table 3
below.
3TABLE 3 Relative Tmax Cmax AUC 0-36 h bioavailability (h) (ng/ml)
(ng .multidot. h/ml) (%) Glucophage 3.5 1280 10 500 100
Microcapsules 7.1 1015 9660 92 of example 2
[0127] The microcapsules of the invention thus represent a
significant overhang in the field of the administration of
metformin by the oral route for the treatment of diabetes.
* * * * *